I see this Perspective article at J. Med. Chem. as a sort of headstone for the field of cholesteryl ester transfer protein inhibitors. That’s been a long-running saga in the drug industry, and we have the enormous success of the statin drugs to thank for that. Statins (HMG-CoA-reductase inhibitors) of course lower LDL, the so-called “bad” cholesterol, and they do that very well indeed. Statin use is definitely associated with a notably lower risk for cardiovascular mortality in a number of large patient populations of different ages, and the hope has always been that some means of elevating HDL (“good cholesterol”) would have similar benefits and quite possibly additive ones to statin treatment. In the early 2000s this hope was particularly acute at Pfizer, whose Lipitor was heading for patent expiration.
Inhibition of CETP was considered the most direct route to raising HDL – this would keep HDL from being “drained off” into other lipoprotein forms. Pfizer had torcetrapib, which was (to my knowledge) their biggest clinical development program ever, and the hopes were that a combination therapy of that and Lipitor would be the cardiovascular wonder pill. But torcetrapib completely wiped out, with the treatment group actually showing a slightly higher rate of cardiovascular mortality, a result that left Pfizer’s cardiovascular pipeline totally naked to the Lipitor expiration and sowed fear and confusion among the other companies who were also working in that space. Roche’s dalcetrapib then failed a few years later. And then Eli Lilly’s evacetrapib failed a few years after that. Finally, Merck came in with anacetrapib, which actually seemed to work – a bit.
The thing is, all these compounds were letdowns in their own particular way. Torcetrapib, as mentioned, killed people off. Atherosclerosis in its treatment group was not really slowed down, and the compound had a side effect of raising blood pressure, which is exactly what you don’t want in this patient population. Dalcetrapib didn’t have that effect, fortunately, but it was dropped due to sheer lack of meaningful efficacy. Evacetrapib did not show that blood pressure problem either, and had even more impressive HDL-raising and LDL-lowering effects than the Pfizer compound. The problem was that it also did nothing at all for the patients in the clinic – the treatment group looked startlingly similar to the controls. And although Merck showed some reduction in cardiovascular events over a multiyear study, it was nowhere near as large as what you can get from taking a statin (and most of those are now cheap generics). The company decided not to even bother trying for FDA approval.
It has to be mentioned that none of these compounds will ever win a molecular beauty contest. The new article goes into an attempt by Merck to make anacetrapib more structurally appealing by introducing some polarity, but there’s only so much you can do with a binding site like CETP’s. I have never seen a target that loves heavily fluorinated compounds more. And it has to be remembered that evacetrapib had a carboxylic acid of its own, not that that saved it. But as the article shows, MK-8262 is probably the best CETP compound ever disclosed – it has a larger safety window, and is active at far lower doses than other compounds (including anacetrapib). But after a Phase I trial, Merck decided against going any further, and that surely says a lot.
Other smaller companies are still chasing the dream, in one form or another. New Amersterdam Pharma picked up an older Amgen compound and is apparently trying to use it more as an alternative LDL-lowering agent in a smaller patient population that still isn’t served by exisiting drugs, for example. So in the best case, a CETP inhibitor might eventually make it as a niche drug, several steps back from the front line, which is not exactly what anyone was picturing 20 years ago. It’s hard to even estimate the amount of time, effort, and money that has gone into this field over the years, most of which has gone into showing us that we don’t know as much about human lipoproteins as we thought we did. It’s been a hard lesson.
